Interaction of PP2A catalytic subunit with Rb2/p130 is required for all-trans retinoic acid suppression of ovarian carcinoma cell growth
Interaction of PP2A catalytic subunit with Rb2/p130 is required for all-trans retinoic acid suppression of ovarian carcinoma cell growth
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DOI：
10.1002/jcp.20490
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发表时间：
2006-02-01
影响因子：
5.6
通讯作者：
Soprano, KJ
中科院分区：
文献类型：
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作者：
Purev, E;Giordano, A;Soprano, KJ
全反式维甲酸（ATRA）治疗导致CAOV3卵巢癌细胞在GO/G1期生长停滞，Rb2/p130蛋白水平升高。PP2A是一种丝氨酸/苏氨酸磷酸酶，结合并使Rb2/p130去磷酸化，从而延长Rb2/p130在细胞中的半衰期。为了进一步表征Rb2/p130与PP2A在ATRA作用下的相互作用，我们检测了PP2A的翻译后修饰。ATRA处理导致PP2A催化亚基（PP2Ac）的低磷酸化，这与PP2A活性增加相关。此外，PP2Ac的n端直接与Rb2/p130的c端NLS序列结合。此外，与亲本CAOV3细胞相比，转染了仅由wt c端组成的截断Rb2/p130构建体的CAOV3细胞生长更有攻击性，对ATRA治疗的敏感性更低。相比之下，CAOV3细胞转染截断的Rb2/p130构建体仅包含NLS位点突变的c端，并且不能与PP2A相互作用，与亲本CAOV3细胞一样对ATRA处理敏感。这些研究表明，ATRA治疗通过涉及PP2A的一种新的转录后机制抑制CAOV3细胞的生长。
All-trans retinoic acid (ATRA) treatment causes CAOV3 ovarian carcinoma cells to growth arrest in the GO/G1 phase and to elevate the level of Rb2/p130 protein. PP2A, a serine/threonine phosphatase, binds and dephosphorylates Rb2/p130, thereby increasing the half-life of Rb2/p130 in the cell. In order to further characterize the interaction between Rb2/p130 and PP2A upon ATRA treatment, we examined the posttranslational modification of PP2A. ATRA treatment leads to hypophosphorylation of PP2A catalytic subunit (PP2Ac) that correlates with increased PP2A activity. In addition, the N-terminus of PP2Ac binds directly to NLS sequences located in the C-terminus of Rb2/p130. Furthermore, CAOV3 cells transfected with a truncated Rb2/p130 construct Consisting Of only the wt C-terminus grew more aggressively and were less sensitive to ATRA treatment when compared to parental CAOV3 cells. In contrast, CAOV3 cells transfected with a truncated Rb2/p130 construct consisting of only the C-terminus in which the NLS sites were mutated and which could not interact with PP2A, were as sensitive to ATRA treatment as parental CAOV3 cells. These Studies Suggest that ATRA treatment suppresses the growth of CAOV3 cells via a novel posttranscriptional mechanism involving PP2A.